Program Director/Principal Investigator (Last, First, Middle): El-Chemaly, Souheil, Y Abstract Lung transplantation remains the only therapy proven to prolong survival and improve quality of life in advanced lung diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. The median survival after transplantation is currently 5.3 years. Little is known about the importance and function of the lymphatic circulation after graft has been implanted and subjects develop acute and/or chronic rejection. A key question is whether post-transplantation lymphangiogenesis is detrimental (e.g. by promoting antigen presentation within draining lymph nodes and stimulating alloimmune responses) or beneficial (e.g. by promoting efficient inflammatory cell clearance). One key molecule is Hyaluronan (HA) which plays critical roles in lung injury and repair and importantly, HA plays a role in transplant rejection. The turnover of HA (several grams/day in humans) occurs primarily in the lymphatics that catabolize approximately 85% of HA. Lymphatic vessel endothelial HA receptor (LYVE-1) is an endocytic receptor for HA on the surface of lymphatic endothelial cells (LEC). In compelling published and preliminary data, we show that in mice recipient of an allogeneic lung graft there is a decrease in lymphatic vessels density in acute rejection. Importantly, stimulating lymphangiogenesis after rejection has been established resulted in improved rejection and lung allograft function. Importantly, the beneficial effects of induction of lymphangiogenesis were abrogated by co-treatment with LYVE-1 function blocking antibodies, suggesting important role(s) for LYVE-1 in inflammatory lung conditions. Based on these findings we propose as a guiding hypothesis that re-establishing the integrity of the lymphatic vasculature through donor lymphatic endothelial cells is critical for HA clearance and the resolution of acute lung rejection. Key corollaries are that targeting the lymphatic vasculature will have clinical efficacy in lung transplant; and that lymphatic-dependent molecules are detectable in the lung microenvironment and in sera of patients with acute lung rejection. To address our hypotheses, we propose these Specific Aims: Aim 1: To identify the origin of lymphatic endothelial cells in lymphatic vessel regeneration after lung transplantation. To determine mechanisms whereby lymphangiogenesis protects against lung allograft rejection. Aim 3: To demonstrate that lymphatic specific changes in lung tissue and peripheral blood can predict acute lung rejection and response to therapy. If successful, this research will provide new insights into the mechanisms underlying the influence of lymhangiogenesis on lung tissue and the role the lymphatic circulation plays in vivo in lung rejection. In addition, it will pave the way for the development of novel strategies to treat acute rejection in lung transplant recipients. PHS 398/2590 (Rev. 06/09) Research strategy Page